| 29177092 |
Genome-guided identification of novel head-to-tail cyclized antimicrobial peptides, exemplified by the discovery of pumilarin |
10.1099/mgen.0.000134. |
Microb Genom |
Genome-guided identification of novel head-to-tail cyclized antimicrobial peptides, exemplified by the discovery of pumilarin
Abstract
- The need for novel antibiotics in an era where antimicrobial resistance is on the rise, and the number of new approved antimicrobial drugs reaching the market is declining, is evident. The underused potential of post-translationally modified peptides for clinical use makes this class of peptides interesting candidates. In this study, we made use of the vast amounts of available genomic data and screened all publicly available prokaryotic genomes (~3000) to identify 394 novel head-to-tail cyclized antimicrobial peptides. To verify these results, we isolated and characterized a novel antimicrobial peptide from that we named pumilarin. Pumilarin was demonstrated to have a circular structure and showed antimicrobial activity against several indicator strains, including pathogens.
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| 29212705 |
Update from a 12-Year Nationwide Fungemia Surveillance: Increasing Intrinsic and Acquired Resistance Causes Concern |
10.1128/JCM.01564-17. |
J Clin Microbiol |
Update from a 12-Year Nationwide Fungemia Surveillance: Increasing Intrinsic and Acquired Resistance Causes Concern
Abstract
- New data from the years 2012 to 2015 from the Danish National Fungemia Surveillance are reported, and epidemiological trends are investigated in a 12-year perspective (2004 to 2015). During 2012 to 2015, 1,900 of 1,939 (98%) fungal bloodstream isolates were included. The average incidence was 8.4/100,000 inhabitants, and this appears to represent a stabilizing trend after the increase to 10.1/100,000 in 2011. The incidence was higher in males than females (10.0 versus 6.8) and in patients above 50 years, and those changes were mainly driven by an increasing incidence among 80-to-89-year-old males (65.3/100,000 in 2014 to 2015). The proportion of isolates decreased from 2004 to 2015 (64.4% to 42.4%) in parallel with a doubling of the proportion of isolates (16.5% to 34.6%, < 0.0001). was more common among females (34.0% versus 30.4% in males). Following an increase in 2004 to 2011, the annual drug use stabilized during the last 2 to 3 years of that time period but remained higher than in other Nordic countries. This was particularly true for the fluconazole and itraconazole use in the primary health care sector, which exceeded the combined national levels of use of these compounds in each of the other Nordic countries. Fluconazole susceptibility decreased (68.5%, 65.2%, and 60.6% in 2004 to 2007, 2008 to 2011, and 2012 to 2015, respectively, < 0.0001), and echinocandin resistance emerged in (0%, 0.6%, and 1.7%, respectively, < 0.001). Amphotericin B susceptibility remained high (98.7%). Among 16 (2.7%) echinocandin-resistant isolates (2012 to 2015), 13 harbored FKS mutations and 5 (31%) were multidrug resistant. The epidemiological changes and the increased incidence of intrinsic and acquired resistance emphasize the importance of continued surveillance and of strengthened focus on antifungal stewardship.
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| 29275987 |
Influence of hydrocarbon-stapling on membrane interactions of synthetic antimicrobial peptides |
10.1016/j.bmc.2017.10.020. |
Bioorg Med Chem |
Influence of hydrocarbon-stapling on membrane interactions of synthetic antimicrobial peptides
Abstract
- Cyclization has been recognized as a valuable technique for increasing the efficacy of small molecule and peptide therapeutics. Here we report the application of a hydrocarbon staple to a rationally-designed cationic antimicrobial peptide (CAP) that acquires increased membrane targeting and interaction vs. its linear counterpart. The previously-described CAP, 6K-F17 (KKKKKK-AAFAAWAAFAA-NH) was used as the backbone for incorporation of an i to i + 4 helical hydrocarbon staple through olefin ring closing metathesis. Stapled versions of 6K-F17 showed an increase in non-selective membrane interaction, where the staple itself enhances the degree of membrane interaction and rate of cell death while maintaining high potency against bacterial membranes. However, the higher averaged hydrophobicity imparted by the staple also significantly increases toxicity to mammalian cells. This deleterious effect is countered through stepwise reduction of the stapled 6K-F17's backbone hydrophobicity through polar amino acid substitutions. Circular dichroism assessment of secondary structure in various bacterial membrane mimetics reveals that a helical structure may improve - but is not an absolute requirement for - antimicrobial activity of 6K-F17. Further, phosphorus-31 static solid state NMR spectra revealed that both non-toxic stapled and linear peptides bind bacterial membranes in a similar manner that does not involve a detergent-like mechanism of lipid removal. The overall results suggest that the technique of hydrocarbon stapling can be readily applied to membrane-interactive CAPs to modulate how they interact and target biological membranes.
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| 29277569 |
Membrane permeabilization design of antimicrobial peptides based on chikungunya virus fusion domain scaffold and its antibacterial activity against gram-positive Streptococcus pneumoniae in respiratory infection |
10.1016/j.biochi.2017.12.007. |
Biochimie |
Membrane permeabilization design of antimicrobial peptides based on chikungunya virus fusion domain scaffold and its antibacterial activity against gram-positive Streptococcus pneumoniae in respiratory infection
Abstract
- The structural dynamics of membrane permeabilization are investigated systematically and compared between viral fusion peptides (VFPs) and antimicrobial peptides (AMPs). It is revealed that the permeabilization process can be divided into two phases: a fast motion phase in water (first phase) and a slow diffusion phase in lipid (second phase). Difference in peptide permeability to neutrally or weakly charged mammalian membrane and to negatively charged bacterial membrane is primarily determined by the first phase, which is dominated by the direct electrostatic interaction between peptide and the hydrophilic surface of membranes. With the harvested knowledge we attempt to rationally design anti-Gram-positive AMPs based on the VFP scaffold of Chikungunya virus fusion domain, which is an 18-mer polypeptide segment (VT18, VYPFMWGGAYCFCDAENT) located in the structural glycoprotein E1 of viral envelope. Our simulations and previous NMR study suggest that the isolated VT18 peptide can be well structured into a double-stranded β-sheet conformation in water, but would become intrinsically disordering in lipid. Converting the negatively charged VT18 (charge = -2) to two positively charged peptides VT18-KKLV (VYPFMWGGAYCFCKAKLV-NH) (charge = +3) and VT18-CAKKLV (VYPFCWGGAYAFCKAKLV-NH) (charge = +3) by residue substitution and C-terminal amidation can largely promote peptide approaching to bacterial membrane surface, thus rendering the peptide with a substantially increased antibacterial activity against Gram-positive Streptococcus pneumoniae (MIC changes from >200 to 52-105 and 58-90 μg/ml, respectively). A further cyclization of linear peptide VT18-CAKKLV by adding a disulfide bond across its two strand arms, which results in a cyclic peptide cVT18-CAKKLV () (charge = +3), can effectively stabilize the peptide β-sheet conformation in lipid, thus improving its membrane compatibility in second phase and enhancing its antibacterial potency (MIC = 35-67 μg/ml). We also demonstrated that the designed AMPs have no or only a moderate cytotoxic effect and hemolytic activity on human normal cells.
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| 29307492 |
Discovery of Next-Generation Antimicrobials through Bacterial Self-Screening of Surface-Displayed Peptide Libraries |
10.1016/j.cell.2017.12.009. |
Cell |
Discovery of Next-Generation Antimicrobials through Bacterial Self-Screening of Surface-Displayed Peptide Libraries
Abstract
- Peptides have great potential to combat antibiotic resistance. While many platforms can screen peptides for their ability to bind to target cells, there are virtually no platforms that directly assess the functionality of peptides. This limitation is exacerbated when identifying antimicrobial peptides because the phenotype, death, selects against itself and has caused a scientific bottleneck that confines research to a few naturally occurring classes of antimicrobial peptides. We have used this seeming dissonance to develop Surface Localized Antimicrobial Display (SLAY), a platform that allows screening of unlimited numbers of peptides of any length, composition, and structure in a single tube for antimicrobial activity. Using SLAY, we screened ∼800,000 random peptide sequences for antimicrobial function and identified thousands of active sequences, dramatically increasing the number of known antimicrobial sequences. SLAY hits present with different potential mechanisms of peptide action and access to areas of antimicrobial physicochemical space beyond what nature has evolved. VIDEO ABSTRACT.
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| 29324395 |
Effects of lanthanum on Microcystis aeruginosa: Attention to the changes in composition and content of cellular microcystins |
10.1016/j.aquatox.2018.01.007. |
Aquat Toxicol |
Effects of lanthanum on Microcystis aeruginosa: Attention to the changes in composition and content of cellular microcystins
Abstract
- Algal blooms threaten human health and aquatic ecosystem through the production of microcystins (MCs) by toxic strains. The accumulation of rare earth elements (REEs) in water affects the growth and physiological activities of algae. However, whether or how REEs affect cellular microcystins (MCs) is largely unknown. In this study, the effects of lanthanum ion [La(III)], a type of REE, on the MCs in Microcystis aeruginosa were investigated, and the mechanism of the effect was analyzed using ecological stoichiometry. The different concentrations of La(III) were selected to correlate environmental pollution status. Low-dose La(III) (0.2, 2.0, and 4.0 μM) exposure increased the total content of MCs and the percentage contents of microcystin-YR (MC-YR) and microcystin-LW (MC-LW) and decreased the percentage content of microcystin-LR (MC-LR). High-dose La(III) (8.0, 20, 40, and 60 μM) exposure decreased the total content of the MCs, increased the percentage content of MC-LR, and decreased the percentage contents of MC-YR and MC-LW. The changes in the total MCs content were positively associated with the ratios of C:P and N:P in algal cells. The composition of MCs was dependent on the ratio of C:N in algal cells; for example, the percentage content of MC-LR decreased and the percentage content of MC-YR and MC-LW increased as the ratio of C:N in algal cells increased. In conclusion, La(III) could affect the content and composition of MCs via changes in the growth and chlorophyll-a content of Microcystis aeruginosa, and these effects depended on the ratios of C:P, N:P, and C:N in Microcystis aeruginosa. Such changes may influence the toxicity of Microcystis blooms. The results provides a new insight into the mechanism of REEs effects on algal toxins and provide references for evaluating environmental risks of REEs pollution in aquatic ecosystems.
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| 29343792 |
Prebiotic formation of cyclic dipeptides under potentially early Earth conditions |
10.1038/s41598-018-19335-9. |
Sci Rep |
Prebiotic formation of cyclic dipeptides under potentially early Earth conditions
Abstract
- Cyclic dipeptides, also known as 2,5-diketopiperazines (DKPs), represent the simplest peptides that were first completely characterized. DKPs can catalyze the chiral selection of reactions and are considered as peptide precursors. The origin of biochemical chirality and synthesis of peptides remains abstruse problem believed to be essential precondition to origin of life. Therefore, it is reasonable to believe that the DKPs could have played a key role in the origin of life. How the formation of the DKPs through the condensation of unprotected amino acids in simulated prebiotic conditions has been unclear. Herein, it was found that cyclo-Pro-Pro could be formed directly from unprotected proline in the aqueous solution of trimetaphosphate (Pm) under mild condition with the yield up to 97%. Other amino acids were found to form proline-containing DKPs under the same conditions in spite of lower yield. During the formation process of these DKPs, Pm promotes the formation of linear dipeptides in the first step of the mechanism. The above findings are helpful and significant for understanding the formation of DKPs in the process of chemical evolution of life.
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| 29345033 |
Total Synthesis and Conformational Study of Callyaerin A: Anti-Tubercular Cyclic Peptide Bearing a Rare Rigidifying (Z)-2,3- Diaminoacrylamide Moiety |
10.1002/anie.201712792. |
Angew Chem Int Ed Engl |
Total Synthesis and Conformational Study of Callyaerin A: Anti-Tubercular Cyclic Peptide Bearing a Rare Rigidifying (Z)-2,3- Diaminoacrylamide Moiety
Abstract
- The first synthesis of the anti-TB cyclic peptide callyaerin A (1), containing a rare (Z)-2,3-diaminoacrylamide bridging motif, is reported. Fmoc-formylglycine-diethylacetal was used as a masked equivalent of formylglycine in the synthesis of the linear precursor to 1. Intramolecular cyclization between the formylglycine residue and the N-terminal amine in the linear peptide precursor afforded the macrocyclic natural product 1. Synthetic 1 possessed potent anti-TB activity (MIC =32 μm) while its all-amide congener was inactive. Variable-temperature NMR studies of both the natural product and its all-amide analogue revealed the extraordinary rigidity imposed by this diaminoacrylamide unit on peptide conformation. The work reported herein pinpoints the intrinsic role that the (Z)-2,3-diaminoacrylamide moiety confers on peptide bioactivity.
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| 29400964 |
Total Synthesis of Scytonemide A Employing Weinreb AM Solid-Phase Resin |
10.1021/acs.jnatprod.7b00912. |
J Nat Prod |
Total Synthesis of Scytonemide A Employing Weinreb AM Solid-Phase Resin
Abstract
- The human 20S proteasome inhibitor scytonemide A (1), a macrocyclic imine originally isolated from the cyanobacterium Scytonema hofmanni, was synthesized via a biomimetic solid-phase peptide synthesis (SPPS) approach employing the Weinreb AM resin. Utilizing this approach, cyclization of the protected heptapeptide via formation of the imine bond occurred spontaneously upon cleavage from the resin in the presence of a reducing agent and subsequent aqueous workup. The final deprotection step necessary to produce the natural product was accomplished under slightly basic conditions, facilitating cleavage of the silyl ether group while leaving the macrocycle intact. Purification of the synthetic scytonemide A was accomplished via normal-phase flash column chromatography, potentially facilitating larger scale preparation of the compound necessary for future mechanistic and SAR studies. The structure of the target compound was confirmed by NMR spectroscopy, which also shed light on differences in the spectroscopic data obtained for the synthetic and natural scytonemide A samples for some of the amide and alcohol signals in the H NMR spectrum.
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| 29431987 |
Solid-Phase Synthesis and Antibacterial Activity of Cyclohexapeptide Wollamide B Analogs |
10.1021/acscombsci.7b00189. |
ACS Comb Sci |
Solid-Phase Synthesis and Antibacterial Activity of Cyclohexapeptide Wollamide B Analogs
Abstract
- Herein we report the antibacterial structure-activity relationships of cyclic hexapeptide wollamide analogs derived from solid-phase library synthesis. Wollamide B, a cyclic hexapeptide natural product, has been previously found to have activity against Mycobacterium bovis. To further evaluate its antimycobacterial/antibacterial potential, 27 peptides including wollamides A/B, and desotamide B, were synthesized and subsequently tested against a panel of clinically significant bacterial pathogens. Biological evaluation revealed that the cyclic scaffold, amide functionality in position I, tryptophan residue in position V, and the original stereochemistry pattern of the core scaffold were key for antituberculosis and/or antibacterial activity. In addition, against M. tuberculosis and Gram-positive bacteria, residues in position II and/or VI greatly impacted antibacterial activity and selectivity. Wollamides A (3) and B (2) along with their corresponding II (l-Leu) analog 10 retained the most promising antituberculosis activity, with the lowest minimum inhibitory concentration (MIC) against virulent M. tuberculosis H37Rv (MIC = 1.56 μg/mL), as well as desirable selectivity indices (>100). Importantly, the antimicrobial activities of wollamides A and B do not result from disruption of the bacterial membrane, warranting further investigation into their mechanism of action.
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| 29437621 |
Pharmacokinetics and Safety of Intravenous Murepavadin Infusion in Healthy Adult Subjects Administered Single and Multiple Ascending Doses |
10.1128/AAC.02355-17. |
Antimicrob Agents Chemother |
Pharmacokinetics and Safety of Intravenous Murepavadin Infusion in Healthy Adult Subjects Administered Single and Multiple Ascending Doses
Abstract
- Murepavadin is the first in class of the outer membrane protein-targeting antibiotics (OMPTA) and a pathogen-specific peptidomimetic antibacterial with a novel, nonlytic mechanism of action targeting Murepavadin is being developed for the treatment of hospital-acquired bacterial pneumonia (HABP) and ventilator-associated bacterial pneumonia (VABP). The pharmacokinetics (PK) and safety of single and multiple doses of murepavadin were investigated in healthy male subjects. Part A of the study was a double-blind, randomized, placebo-controlled, single-ascending-dose investigation in 10 sequential cohorts where each cohort comprised 6 healthy male subjects; 4 subjects were randomized to murepavadin, and 2 subjects were randomized to placebo. Part B was a double-blind, randomized, placebo-controlled, multiple-ascending-dose investigation in 3 sequential cohorts. After a single dose of murepavadin, the geometric mean half-life (2.52 to 5.30 h), the total clearance (80.1 to 114 ml/h/kg), and the volume of distribution (415 to 724 ml/kg) were consistent across dose levels. The pharmacokinetics of the dosing regimens evaluated were dose proportional and linear. Murepavadin was well tolerated, adverse events were transient and generally mild, and no dose-limiting toxicity was identified.
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| 29451043 |
Murepavadin: a new antibiotic class in the pipeline |
10.1080/14787210.2018.1441024. |
Expert Rev Anti Infect Ther |
Murepavadin: a new antibiotic class in the pipeline
Abstract
- With the increase in multi-drug resistant P. aeruginosa, antimicrobials with a novel mechanism of action are needed that can target these infections. Areas covered: Intravenous murepavadin is in Phase 3 development for the treatment of HABP/VABP due to P. aeruginosa. This paper summarizes the available information on the discovery, the in vitro activity, pharmacokinetic and pharmacodynamic properties and the clinical pharmacology of murepavadin to date. Expert commentary: P. aeruginosa has an intrinsic resistance to many antibiotics due to high cellular impermeability and efficient drug efflux mechanisms, and the recent increase in prevalence of multidrug-resistant P. aeruginosa infections are particularly threatening in ICU settings. Murepavadin is a pathogen specific antimicrobial peptidomimetic with a novel, non-lytic mechanism of action, and is the first in class of outer membrane protein targeting antibiotics which are being developed. Murepavadin displays a potent in vitro activity including carbapenemase-producing and colistin-resistant P. aeruginosa. Murepavadin is active in pre-clinical animal models including infections with XDR isolates. The Pharmacokinetics is well characterized including subjects with impaired renal function and patients with VABP. Intravenous murepavadin is currently under clinical development for the treatment of HABP/VABP due to P. aeruginosa infection.
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| 29472927 |
Genome-Wide Identification of Destruxin A-Responsive Immunity-Related MicroRNAs in Diamondback Moth, |
10.3389/fimmu.2018.00185. |
Front Immunol |
Genome-Wide Identification of Destruxin A-Responsive Immunity-Related MicroRNAs in Diamondback Moth,
Abstract
- , a global key pest, is one of the major lepidopteran pests of cruciferous vegetables owing to its strong ability of resistance development to a wide range of insecticides. Destruxin A, a mycotoxin of the entomopathogenic fungus, , has broad-spectrum insecticidal effects and has been used as an alternative control strategy to reduce harmful effects of insecticides. However, microRNA (miRNA)-regulated reactions against destruxin A have not been elucidated yet. Therefore, here, to identify immunity-related miRNAs, we constructed four small RNA libraries from destruxin A-injected larvae of at three different time courses (2, 4, and 6 h) with a control, and sequenced by Illumina. Our results showed that totally 187 known and 44 novel miRNAs were identified in four libraries by bioinformatic analysis. Interestingly, among differentially expressed known miRNAs, some conserved miRNAs, such as miR-263, miR-279, miR-306, miR-2a, and miR-308, predicted to be involved in regulating immunity-related genes, were also identified. Worthy to mention, miR-306 and miR-279 were also listed as common abundantly expressed miRNA in all treatments. The Kyoto Encyclopedia of Genes and Genomes pathway analysis also indicated that differentially expressed miRNAs were involved in several immunity-related signaling pathways, including toll signaling pathway, IMD signaling pathway, JAK-STAT signaling pathway, and cell adhesion molecules signaling pathway. To the best of our knowledge, this is the first comprehensive report of destruxin A-responsive immunity-related miRNAs in . Our findings will improve in understanding the role of destruxin A-responsive miRNAs in the host immune system and would be useful to develop biological control strategies for controlling .
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| 29486356 |
Rezafungin (CD101), a next-generation echinocandin: A systematic literature review and assessment of possible place in therapy |
10.1016/j.jgar.2018.02.013. |
J Glob Antimicrob Resist |
Rezafungin (CD101), a next-generation echinocandin: A systematic literature review and assessment of possible place in therapy
Abstract
- Rezafungin (CD101) is a novel echinocandin currently under development. The purpose of this study was to perform a systematic literature review of published evidence on rezafungin and an antimicrobial stewardship audit of real-world use of echinocandins to determine areas of unmet medical needs and potential places in therapy for rezafungin.
The systematic literature review identified 8 peer-reviewed manuscripts and 19 separate abstracts. A stewardship audit was performed on hospitalised patients receiving echinocandins to better understand potential future areas of use for rezafungin.
Rezafungin is a cyclic hexapeptide with a lipophilic tail derived from anidulafungin, with a choline moiety at the C5 ornithine position resulting in increased in vitro and in vivo stability compared with other echinocandins. Microbiological data showed similar susceptibility and resistance development between rezafungin and other echinocandins. Rezafungin has a long half-life (80h) and a favourable safety profile that allows for high doses (up to 400mg) given once weekly. A phase 2 study is ongoing. The antimicrobial stewardship audit of echinocandin identified several areas of possible use for rezafungin, including patients receiving daily echinocandins for >7 days, patients who remained in the hospital to complete a full course of daily echinocandin therapy, and patients who required an echinocandin scheduled via an infusion clinic after discharge.
Rezafungin is a novel echinocandin currently in phase 2 studies, differentiated by a long half-life that allows once-weekly dosing and a safety profile that allows higher doses. Several potential areas of use for rezafungin were identified.
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| 29499224 |
A critical role for IL-18 in transformation and maturation of naive eosinophils to pathogenic eosinophils |
10.1016/j.jaci.2018.02.011. |
J Allergy Clin Immunol |
A critical role for IL-18 in transformation and maturation of naive eosinophils to pathogenic eosinophils
Abstract
- The current studies demonstrate a critical role of IL-18 in transforming IL-5 generated naïve eosinophils into the distinct inflammatory CD101CD274 expressing mature and activated tissue eosinophils that promote disease pathogenesis.
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